ACTIVITY OF SR-142801 AT PERIPHERAL TACHYKININ RECEPTORS

The pharmacological profile of the novel tachykinin NK3 receptor antag onist SR 142801, ((S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl) pipe ridin-3-yl) ropyl)-4-phenylpiperidin-4-yl)-N-methylacetamide), was stu died at tachykinin NK1, NK2 and NK3 receptors, in several in vitro bio assays. In the guinea-pig isolated ileum longitudinal muscle preparati on, SR 142801 (10 nM-1 mu M) caused an insurmountable antagonism of ta chykinin NK3 receptor-mediated contractions produced by senktide (appa rent pK(B) = 9.27). The blockade induced by SR 142801 was essentially irreversible, since it was not removed by washout (up to 2 h) and was increased by prolonging the incubation from 15 to 120 min. SR 142801 s howed similar antagonist potency at rat tachykinin NK3 receptors (port al vein) and rabbit tachykinin NK2 receptors (pulmonary artery) (pK(B) = 7.49 and 7.66, respectively), whereas it was distinctly less potent at hamster tachykinin NK2 receptors (trachea; pK(B) = 6.84) and inact ive at guinea-pig tachykinin NK1 receptors (ileum, longitudinal muscle ). In the guinea-pig whole ileum SR 142801 (100 nM) did not affect the contraction produced by capsaicin (1 mu M). The combined SR 142801 pr etreatment and tachyphylaxis of neuronal CGRP (calcitonin gene-related peptide) receptors produced a slight (about 25%), but significant red uction of the response to capsaicin, suggesting that tachykinin NK3 re ceptors play a minor role in capsaicin-induced neuronal excitation of afferent nerves in the guinea-pig ileum.